AU701883B2 - Process for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer - Google Patents
Process for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer Download PDFInfo
- Publication number
- AU701883B2 AU701883B2 AU10018/97A AU1001897A AU701883B2 AU 701883 B2 AU701883 B2 AU 701883B2 AU 10018/97 A AU10018/97 A AU 10018/97A AU 1001897 A AU1001897 A AU 1001897A AU 701883 B2 AU701883 B2 AU 701883B2
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- Australia
- Prior art keywords
- general formula
- compound
- reaction
- group
- alkyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 48
- -1 hetero-bicyclic alcohol enantiomer Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 230000000707 stereoselective effect Effects 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
- 239000000543 intermediate Substances 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 125000006239 protecting group Chemical group 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- 125000005843 halogen group Chemical group 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 5
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 75
- 239000002904 solvent Substances 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000006396 nitration reaction Methods 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 7
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000005905 mesyloxy group Chemical group 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 238000007080 aromatic substitution reaction Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- MLGCXEBRWGEOQX-UHFFFAOYSA-N tetradifon Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)C1=CC(Cl)=C(Cl)C=C1Cl MLGCXEBRWGEOQX-UHFFFAOYSA-N 0.000 claims description 2
- 208000035217 Ring chromosome 1 syndrome Diseases 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 113
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 239000010410 layer Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 229940093499 ethyl acetate Drugs 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- IIFFFBSAXDNJHX-UHFFFAOYSA-N 2-methyl-n,n-bis(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)CC(C)C IIFFFBSAXDNJHX-UHFFFAOYSA-N 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 229940100198 alkylating agent Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- OYROQHDNOMFATQ-UHFFFAOYSA-N 4-benzyl-5-chloro-3-nitrobenzene-1,2-diol Chemical compound [O-][N+](=O)C1=C(O)C(O)=CC(Cl)=C1CC1=CC=CC=C1 OYROQHDNOMFATQ-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940086542 triethylamine Drugs 0.000 description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical group COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 3
- YUMZFEGWCGNXHR-UHFFFAOYSA-N 5-chloro-3-nitrobenzene-1,2-diol Chemical compound OC1=CC(Cl)=CC([N+]([O-])=O)=C1O YUMZFEGWCGNXHR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- RNVYQYLELCKWAN-RXMQYKEDSA-N [(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@@H](CO)O1 RNVYQYLELCKWAN-RXMQYKEDSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 3
- 229940073608 benzyl chloride Drugs 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical class [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 description 3
- MGLATQBXHTZVGI-UHFFFAOYSA-N (7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol Chemical compound C1=C(Cl)C=C([N+]([O-])=O)C2=C1OC(CO)CO2 MGLATQBXHTZVGI-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- CMKPZIPXIPGPDE-UHFFFAOYSA-N 4-chloro-2-nitro-6-phenylmethoxyphenol Chemical compound C1=C(Cl)C=C([N+]([O-])=O)C(O)=C1OCC1=CC=CC=C1 CMKPZIPXIPGPDE-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- RNVYQYLELCKWAN-YFKPBYRVSA-N [(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@H](CO)O1 RNVYQYLELCKWAN-YFKPBYRVSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 150000001983 dialkylethers Chemical class 0.000 description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- SRKDUHUULIWXFT-UHFFFAOYSA-N (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC(C)(C)OC1 SRKDUHUULIWXFT-UHFFFAOYSA-N 0.000 description 1
- RQCZFRALDWUGFF-GFCCVEGCSA-N (2R)-2-[(4-chloro-2-nitro-3-phenylmethoxyphenoxy)methyl]oxirane Chemical compound C([C@H]1CO1)OC1=C(C(=C(C=C1)Cl)OCC1=CC=CC=C1)[N+](=O)[O-] RQCZFRALDWUGFF-GFCCVEGCSA-N 0.000 description 1
- GYZLOYUZLJXAJU-PHDIDXHHSA-N (2s)-2-[[(2s)-oxiran-2-yl]methoxymethyl]oxirane Chemical compound C([C@H]1OC1)OC[C@@H]1CO1 GYZLOYUZLJXAJU-PHDIDXHHSA-N 0.000 description 1
- SYVXVXXEQAIQRM-UHFFFAOYSA-N (6-chloro-3,4-dihydroxy-2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=C(O)C(O)=CC(Cl)=C1C(=O)C1=CC=CC=C1 SYVXVXXEQAIQRM-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical group C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- 150000005529 1,3-benzodioxoles Chemical class 0.000 description 1
- QNRYTNHAAHDNAG-UHFFFAOYSA-N 1,4-benzodioxin-3-ylmethanol Chemical compound C1=CC=C2OC(CO)=COC2=C1 QNRYTNHAAHDNAG-UHFFFAOYSA-N 0.000 description 1
- MOBRMRJUKNQBMY-UHFFFAOYSA-N 1-(chloromethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CCl MOBRMRJUKNQBMY-UHFFFAOYSA-N 0.000 description 1
- VGISFWWEOGVMED-UHFFFAOYSA-N 1-(chloromethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CCl)=C1 VGISFWWEOGVMED-UHFFFAOYSA-N 0.000 description 1
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 1
- DDGRAFHHXYIQQR-UHFFFAOYSA-N 1-chloro-3-(chloromethyl)benzene Chemical compound ClCC1=CC=CC(Cl)=C1 DDGRAFHHXYIQQR-UHFFFAOYSA-N 0.000 description 1
- RSCLKRDPCPYTGC-UHFFFAOYSA-N 156016-33-0 Chemical compound CC(=O)NC1=CC(Cl)=CC([N+]([O-])=O)=C1O RSCLKRDPCPYTGC-UHFFFAOYSA-N 0.000 description 1
- HEJLFBLJYFSKCE-UHFFFAOYSA-N 2',3'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1O HEJLFBLJYFSKCE-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- GWQOQQVKVOOHTI-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-ylmethanol Chemical compound C1=CC=C2OC(CO)COC2=C1 GWQOQQVKVOOHTI-UHFFFAOYSA-N 0.000 description 1
- DTCYSRAEJHGSNY-UHFFFAOYSA-N 2-methoxy-2-(2-methoxypropan-2-yloxy)propane Chemical compound COC(C)(C)OC(C)(C)OC DTCYSRAEJHGSNY-UHFFFAOYSA-N 0.000 description 1
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 1
- YEJJWOUXNCSWDH-UHFFFAOYSA-N 5-benzyl-4-chloro-3-nitrobenzene-1,2-diol Chemical compound [O-][N+](=O)C1=C(O)C(O)=CC(CC=2C=CC=CC=2)=C1Cl YEJJWOUXNCSWDH-UHFFFAOYSA-N 0.000 description 1
- OAHXYWFTOWNMNU-UHFFFAOYSA-N 7-oxabicyclo[4.1.0]hepta-1(6),2,4-triene-4,5-diol Chemical compound OC1=CC=C2OC2=C1O OAHXYWFTOWNMNU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 238000007027 Dakin phenol oxidation reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- NOQXXYIGRPAZJC-SECBINFHSA-N [(2r)-oxiran-2-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@@H]1OC1 NOQXXYIGRPAZJC-SECBINFHSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000012345 acetylating agent Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001346 alkyl aryl ethers Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 150000005524 benzylchlorides Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000002894 chemical waste Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000005205 dihydroxybenzenes Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- NYSDRDDQELAVKP-SFHVURJKSA-N flesinoxan Chemical compound C([C@@H](O1)CO)OC2=C1C=CC=C2N(CC1)CCN1CCNC(=O)C1=CC=C(F)C=C1 NYSDRDDQELAVKP-SFHVURJKSA-N 0.000 description 1
- 229950003678 flesinoxan Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- PUPKPAZSFZOLOR-UHFFFAOYSA-N n,n-dimethylformamide;toluene Chemical compound CN(C)C=O.CC1=CC=CC=C1 PUPKPAZSFZOLOR-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- HHFOOWPWAXNJNY-UHFFFAOYSA-N promoxolane Chemical compound CC(C)C1(C(C)C)OCC(CO)O1 HHFOOWPWAXNJNY-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000003385 ring cleavage reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/06—Six-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Epoxy Compounds (AREA)
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer, characterized in that a substantially pure enantiomer of the general formula <CHEM> wherein X is O, S, NH or N-(C1-C4)alkyl; Y1 and Y2 are each independently hydrogen or substituents selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, formyl, nitro and cyano; the C*-atom has either the R or the S configuration; is prepared from a compound of the general formula <CHEM> wherein R1 is hydrogen or a suitable protective group and R2 is hydrogen or wherein R1 and R2 together form an optionally mono- or di-(C1-C3)alkyl substituted methylene bridge; by the following successive reaction steps: (i) reaction with a compound of the general formula <CHEM> wherein Z is a hydroxy group or a suitable leaving group, R3 is a hydroxy-protective group and R4 is a halogen atom; or wherein R3 and R4 together constitute a valence bond or a biradical of the formula -C(R11)2-O-, wherein R11 is a straight or branched (C1-C4)alkyl group and wherein the C*-atom has either the R or the S configuration; (ii) subjection of the compound formed to a deprotection/ring-closure reaction; (iii) optionally deprotection of the hydroxy group of the ring-closed product. The invention further relates to enantiomerically pure intermediates, the preparation of these intermediates and the preparation of a starting compound.
Description
rsfnc~----
AUSTRALIA
Patents Act COMPLETE SPECIFICATION
(ORIGINAL)
I
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: 4 0P 41
S
Op..
40 Duphar International Research B.V.
Actual Inventor(s): Nicolaas Buizer Chris G. Kruse Klara M. Schenk Belal Shadid Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: PROCESS FOR THE STEREOSELECTIVE HETERO-BICYCLIC ALCOHOL ENANTIOMER PREPARATION OF A Our Ref 476853 POF Code: 1596/46997 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- .y'~hji 1 1 ja DIR0536 Process for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer.
The present invention relates to a process for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer by the use of chiral building blocks. The invention further relates to a process for the preparation of a' starting compound for the reaction with a chiral building block.
Various biologically active substances, which may be used, for example, in pharmaceutical compositions for human or veterinary application, contain a chiral centre in their molecular structure and therefore give I rise to optical isomerism. It is generally known in the art, that often only one of the enantiomers presents the desired optimum biological activity. The presence of the other optical antipode in a composition or agent may cause or invigorate certain side effects and burden the recipient, i.c. the human or animal body. It is generally deemed more and more desirable to administer the biologically active substance in the form of a substantially pure enantiomer, which specifically exhibits 20 the desired biological activity. Therefore, the preparation of substantially enantiopure compound is often an important step in the S.S. preparation process of pharmacologically active substances. In most of the cases the enatiomers are obtained by resolution of a racemate into its enantiomers.
There are several methods available to resolve racemates into their respective enantiomers. The first of these, viz. a resolution based on difference in physical properties, e.g. in crystal structure, is only occasionally applicable.
The second and by far most generally used method of resolution involves a reaction with a commercially available optically active reagent to produce diastereomers, which differ in physical properties. So, the diastereomers obtained in this manner can be separated, e.g. by recrystallization, after which the respective enantiomers can be regenerated by a chemical after-treatment. It will be evident, that such a method of resolving racemates is both labour-intensive and expensive, i.a. on account of the use and recovery of an expensive optically active 2 DIR0536 reagent.
Recently, in a more economical third method of resolution, enzymes are applied to chemically modify one enantiomer of a racemate selectively, followed by a separation of the modified from the unmodified enantiomer.
As an example, Bianchi et al. Org. Chem., 1988, 53, 5531-5534) have reported the use of carboxylic anhydrides as acylating agents in lipasecatalysed selective esterification of racemic alcohols. An improvement of this method is described in the European Patent Application 0605033.
Another method for the production of enantiomers is the use of chiral building blocks. In comparison with the first three mentioned methods, o? 0 this method has the big advantage that the reaction can be carried out in such a way that only or mainly the desired enantiomer is formed. This °°005 prevents the formation of substantial quantities (up to 50%) of the undesired enantiomer, a compound that generally has to be considered as chemical waste or, in the case that racemisation is possible, has to be recycled by one or more laborious steps.
0909 20 One aspect of the present invention is to provide an economically operative process for the stereoselective preparation of a heterocyclic alcohol enantiomer, suitable as an intermediate in the synthesis of pharmacologically active substances such as flesinoxan.
This aspect can be achieved by a process using a chiral building block for the introduction of the chiral centre, which process is characterized according to the present invention, in that a substantially pure enantiomer of the general formula .X CH 2
-OH
Yro
NO
2
(I)
wherein X is O, S, NH or N- alkylr; Y, and Y, are each independently hydrogen or substituents selected from halogen, alkyl, (CQ-C) alkoxy, 3 DIR0536 haloalkyl, formyl, nitro and cyano; the C*-atom has either the R or the S configuration; is prepared from a compound of the general formula YJ X-R Y 2 O-R 2
(II)
wherein: NO 2 X, Yi and Y, have the same meanings as defined above; R, is hydrogen or a suitable protective group; R. is hydrogen; or wherein Ri and RP together form an optionally mono- or di- (C-C)alkyl substituted methylene bridge; by the following successive reaction steps: reaction with a compound of the general formula 0 0 0 (III) 20 wherein: Z is a hydroxy group or a suitable leaving group; R3 is a hydroxy-protective group; R is a halogen atom; or wherein R, and R, together constitute a valence 25 bond or a biradical of the formula -C(Rll) 2 "wherein Rj is straight or branched (C 1
-C
4 alkyl; the C-atom has either the R or the S configuration; after which reaction a compound is formed of the general formula
X-R
0Y R 4
(IV)
wherein: X, Y 1
Y
2
R
3 and R4 have the above meanings; and R, is hydrogen or a protective group; r 4 DIR0536 (ii) subjection of the compound formed to a deprotection/ringclosure reaction; (iii) optionally deprotection of the hydroxy group of the ring-closed product.
The protection of a hydroxy group by a suitable protective group is well known in the art, e.g. as described in the Handbook "Protective Groups in Organic Synthesis" by Greene and Wuts (J.Wiley Sons, Inc., N.Y., 2nd ed. 1991) Examples of suitable protective groups are optionally substituted benzyl, acetyl, butanoyl, optionally substituted benzoyl 2,6-dichlorobenzoyl), methoxy isopropyl (MIP), tert. butyl dimethylsilyl and tetrahydropyranyl. Preferred for protective group Ri a 0* are optionally substituted benzyl and benzoyl. Preferred for protective *o group R 3 is MIP.
*The reaction step between the compounds II and III can be carried out in a homogeneous solvent system, in polar solvents as Nmethylpyrrolidone (NMP), DMSO and DMF or in a heterogeneous apolar solvent/water system with the aid of a phase transfer catalyst and under the influence of a base. The preferred apolar solvent is toluene. Phase transfer catalysts that can be used are tetrabutylammonium salts, *e *preferably tetrabutylammonium hydrogen sulphate. Examples of bases that can be used are K 2
CO
3 NaOH and NaH.
25 When R is hydrogen, the group Z in compound III has to be a suitable leaving group. Examples of suitable leaving groups are halo and sulphonate leaving groups, such as halogen, mesyloxy, tosyloxy and nosyloxy. The preferred leaving group is the nosyloxy group. When R, and R, together form a methylene bridge, Z may be hydroxy.
When the compound IV has been formed, a deprotection/ringclosure reaction (ii) is needed in order to form the ring-closed product.
Removal of all protective groups is necessary. Deprotection of protected groups can be achieved by methods known in the art. The protecting groups can be removed at the same time or successively, dependent on the nature of the protective group. In the case of an ester protective group, basic conditions can be applied, leading to deprotection of both DIR0536 groups and successive ring-closure to the bicyclic moiety. In the case of MIP protection or when R, and R4 together form a biradical of the formula -C(Rn) 2 wherein Rj has the above -defined meaning, the protective group can be removed by acidic conditions as e.g. 45% HBr in acetic acid. The ring-closure reaction is performed by application of basic conditions.
In a suitable embodiment of the method of the present invention, a substantially pure enantiomer of the above general formula I, wherein X is 0, is prepared by the above method, characterized in that a substantially pure enantiomer of the general formula I as defined above, wherein X is 0, is prepared by reaction of a catechol derivative of the general formula
O-RS
y 1
V)
0-H N0 2
S(VI)
:25 0 R
R
wherein: R gop a0R, and R4 have the above meanings; a nd Z is a halo or a suphonate leaving group, preferably selected from tosyloxy, nosyloxy and mesyloxy; after which reaction the inte rmediate obtained, having the general formula
O-R
y, 3 5 0 (VII) arit: Ro Pl susat ay Pur haenaf ro the above aig;eneda foml I hrinX: i Z0is0 is repald or t uhnae meavid, chrucrerably selteda. f whish isperd reaction ofe inemeit obaiedhavin dratie ofene I **..*genalformula
R
YN0 r t g~ 6 DIR0536 is subjected to the successive reaction steps ii) and iii) as defined above.
Suitable chiral building blocks of the general formula VI for performing the above reaction can be depicted by the following formulas: Hal wherein: C' has either the R or the S configuration; Z' has the above meaning, and is preferably nosyloxy or tosyloxy; R is (C-C)alkyl, preferably methyl or isopropyl; and SR,, is a suitable hydroxy-protective group, preferably a f methoxyisopropyl (MIP) group.
Preferred conditions for the reaction of the compound of formula V with the above chiral building blocks are: an organic solvent or solvent mixture, such as toluene, methyl isobutyl ketone (MIBK) or a toluene-DMF S: 20 mixture; reaction temperature between ambient temperature and reflux, preferably reflux; presence of a base, such as NaOH, KOH, K 2
CO
3 or NaH (at least equimolar); and, if desired, the presence of a phase-transfer agent. Suitable phase-transfer agents are quaternary ammonium salts, such as tetrabutylammonium hydrogen sulphate and tetrabutylammonium bromide.
Suitable protecting groups are defined above. As for R 1 preferred for protective group R are optionally substituted benzyl and benzoyl. Most preferred is optionally substituted benzyl. In this case the deprotection of Rs, simultaneously with epoxide or solketal cleavage, is preferably carried out in the presence of a mineral acid, such as HC1 or HEr, in a polar solvent or solvent mixture, such as acetic acid or acetic acid/NMP, at a temperature between ambient temperature and reflux. The subsequent ring-closure reaction can be performed in the same solvent, preferably under the influence of a suitable base, such as KOH, NaOH, etc.
1- 1 serarsr 7 DIR0536 In another, equally attractive embodiment of the present invention, a substantially pure enantiomer of the general formula I as defined above, wherein X is 0, is prepared by reaction of a catechol derivative of the general formula
O-
R
S'
Yi
Y
2 (Va)
S-H
NO
2 wherein: Y, and Y 2 have the meanings given in claim 1; and Rs' is a hydroxy-protective group selected from the group consisting of (Ci-C)alkylcarbonyl and arylcarbonyl, wherein the aryl group is optionally substituted with one or more .:15 substituents selected from the group consisting of (Cl-
C
4 )alkoxy and halogen; with a compound of the general formula r"
(VI)
:20 0 R4 wherein:
R
3
R
3 and PR have the above meanings; and Z' is a halo or a sulphonate leaving group, preferably selected from tosyloxy, nosyloxy and mesyloxy; .25 after which reaction the intermediate obtained, having the general formula 0 CH 2 -ORs' O (VIla)
NO
2 is subjected to deprotection of the hydroxy group of the ring-closed product.
Suitable chiral building blocks of the general formula VI and preferred reaction conditions are the same as for the reaction of compounds with 8 DIR0536 the cvreral formula V, described above.
Preferred hydroxy-protective groups in this reaction are arylcarbonyl groups. The removal of the hydroxy-protective group R' is performed in a manner known in the art.
In another suitable embodiment of the method of the present invention, a substantially pure enantiomer of the above general formula I, wherein X is NH or N- (C -C 4 )alkyl, is prepared by a method as described above, characterized in that a substantially pure enantiomer of the general formula I as defined above, wherein X is NH or N-(Cl-C 4 )alkyl, is prepared by reaction of a compound of the general formula
R
6 (VIII)
Y
2
O-H
wherein: NO 2 Y| and Y 2 have the meanings given above; and is a suitable amino-protective group; i S" '.20 R is hydrogen or (Ca-C 4 )alkyl; with a compound of the general formula j.:z (VI) 0 R :25 wherein: R 3
R
3 and R4 have the above meanings; and Z' is a halo or a sulphonate leaving group, preferably selected from tosyloxy, nosyloxy and mesyloxy; after which reaction the intermediate formed, having the general formula Y T (x) 0 is subjected deprotection of the hydroxy group of the ring-closed
I
4
'I-I
I'
9 DIR0536 product.
Examples of suitable amino-protective groups are acyl groups, such as arylcarbonyl, alkylcarbonyl acetyl) and alkylsulfonyl groups.
Preferred are alkylcarbonyl groups.
The reaction steps can be performed as described above for the formulc I compounds wherein X is O.
In another, equally attractive embodiment of the method of the present invention, a substantially pure enantiomer of the above general formula I, wherein X is 0, can be prepared by reacting a benzodioxole compound of the general formula i 15 O C(XI) o 00
NO
2 wherein: YI and Y 2 have the meanings given above; and 20 R, and R, are each independently hydrogen or methyl; with, as a chiral building block, a compound of the formula a X HO or HOe po *.25 O O O (XIIa) (XIIb) wherein: R is straight or branched (C-C 4 )alkyl.
This reaction is preferably carried out in a polar organic solvent, such as DMF, DMSO, NMP or toluene, in the presence of a base, such as NaOH, KOH, NaH or K 2
CO
3 at a reaction temperature between 0°C and reflux.
In the case of the use of a compound of the formula XIIb, the subsequent solketal ring cleavage and the ring-closure reaction to the formula I compound is performed as described above, viz. by a treatment with mineral acid in e.g. acetic acid, followed by a treatment with aqueous base, e.g. an aqueous NaOH-solution.
i DIR0536 The invention also relates to compounds to be used as new intermediates in the method as described above, such compounds having the general formula X-R
(I
r Y O1 YJ
NO
2 O R 3 These new compound can be prepared as described above, viz. by a method of preparing a compound as defined above, characterized in that a compound of the general formula X-R1'" 15
Y
O-R
2 i(II)
NO
2 i wherein the symbols have the meanings given above; is reacted with a compound of the general formula i (III) .0 R4
R
3 i. wherein the symbols also have the meanings given above.
Furthernore the invention also relates to compounds to be used as new intermediates in the method described above, such compounds having the general formula 0 .*CH 2
-OR
5 Y1 NO2 wherein the symbols have the meanings given above. These new compounds can be prepared as described above, viz. by a method of preparing a compound as defined above, characterized in that a compound of the A V. i 11 DIR0536 general formula i YO-R 5 Y1I
Y
2 (Va)
O-H
NO
2 wherein the symbols have the meanings given above; is reacted with a compound of the general formula z *(VI) 0 R4 R3 15 wherein the symbols also have the meanings given above.
0 For the above-mentioned reaction V VI VII, a suitable monohydroxy-protected catechol derivative of formula V is required as a starting compound. Suitable protecting groups are alkylcarbonyl groups acetyl), (optionally substituted) benzyl groups and trialkylsilyl Egroups.
a The preparation of monoacetates of hydroquinone and catechol has been investigated, according to early publications, with varying results.
sOltcott Am. Chem. Soc. 59, 1937, 392-393) has found, that the monacetylation of these two dihydroxybenzenes can be performed by careful reaction with an acetylating agent, e.g. acetic anhydride, in aqueous alkaline solution. The desired mono-acetate was obtained in a yield of only 20-30%, whereas the major product obtained was the diacetate. Johnston (Chem. Ind. 1982, 1000) has succeeded in improving the formation of the mono-acetate of hydroquinone from hydroquinone and acetic anhydride by using triethyl amine as a base and 4dimethylaminopyridine (DMAP) as a catalyst, in a polar organic solvent, viz. in ethyl acetate solution. Under such reaction conditions, Johnston has succeeded in cbtaining hydroquinone mono-acetatu in yields of 58- 12 DIR0536 i It will be obvious that the above results are also not attractive from an economical point of view for the production of mono-protected dihydroxybenzenes.
It has now been found, as an additional aspect of the present invention, that mono-protected catechol derivatives having the general formula
O-R
Y1 I 1 0Y2 O-H (XIv) NO2 wherein:
Y
1 and Y, have the meanings given above, and 15 PR is an optionally substituted benzoyl group, a (CQ-C 4 alkylcarbonyl group or a tri(C-C4)alkylsilyl group; can easily be prepared in high yields by reaction of a substituted catechol of the general formula 20 20 O-H j (XV) wherein:
Y
1 and Y, have the above meanings, and 25 p and q are 0 or 1; with a compound of the general formula 20 or R,'Hal or (R 1 4 SiHal wherein: is an optionally substituted benzoyl group or a alkylcarbonyl group;
R
14 is (Ci-C 4 )alkyl; and Hal is halogen; in the presence of an organic base, preferably a tert. amine or a mixture of organic bases, in a catalytic amount; r characterized in that the reaction is carried out in an apolar organic 13 DIR0536 solvent or without a solvent, after which the compound obtained, having the general formula
O-R
9
I
I OH (XVIa is successively subjected to an aromatic substitution reaction to introduce substituents Y, and Y, into the aromatic nucleus, if necessary, and to a nitration. j When an acyl protecting group is desired, the mono-acylation reaction is preferably carried out without a solvent, so in a melt, if the reaction mixture is liquid under the reaction conditions applied. The reaction temperature may vary between ambient temperature and approx. 150 0
C,
dependent on the character of the reaction components; in general a *eel slightly elevated reaction temperature is used.
The reaction may also be carried out in an apolar organic solvent, such as a hydrocarbon, e.g. toluene and xylene, or a dialkyl ether, e.g.
methyl tert.-butyl ether (MTBE).
Suitable organic bases for the above monoprotection of catechol are amines, such as triethyl amine (TEA), diethyl amine, triisobutyl amine (TIBA), pyridine, 2,6-lutidine, dimethyl aniline (DMA), DMAP, and mixtures of DMAP with TEA or TIBA. For the above mono-acylation the 25 amine should be present in an at least catalytic amount based on the starting catechol; the starting acylating agent is preferably present in .I a slight equimolar excess. The mono-acylation of catechol can so easily be realized in yields of over 85%, based on starting catechol.
For the formation of the catechol mono (trialkylsilyl) ether various trialkylsilyl halides can be used, such as a tert.-butyl dimethylsilyl halogenide. This reaction can easily be performed in an apolar organic solvent, such as a dialkyl ether, e.g. methyl tert. -butyl ether, in the presence of an equivalent amount of an organic base as defined above. At elevated temperature, e.g. at reflux, the desired monosilyl ether of catechol can be obtained in a yield of over 14 DIR0536 Monoprotection can also be realized by monobenzylation. For the formation of a monobenzyl protected catechol an (optionally substituted) benzylhalogenide, preferably (optionally substituted) benzylchloride is used as a reagent in the presence of a base: Suitable solvents are alcohols. The preferred solvent is methoxyethanol. Alternatively a two phase hydrocarbon/water system, preferably toluene/water, can be used with the aid of a phase transfer catalyst e.g. a tetra-alkylammonium salt. A second alternative is the mono-alkylation without a solvent in the presence of a phase transfer catalyst. Usefull bases are hydroxides and carbonates, such as NaOH, KHCO and K 2 CQ. The addition of a catalytic amount of an iodide can be usefull in order to improve the reaction rate. In this way a mono-alkylation of catechol can be realized in yields over 15 The subsequent introduction of substituents Y 1 and Y 2 if these S" substituents are not yet present during the monoprotection of catechol, as well as the following nitration, is carried out by methods known in the art. The electrophilic aromatic substitution for introducing Yi and Y, is well-known in the art; a chlorination, for example, can easily be performed with a suitable chlorination agent, such as sulphuryl chloride, etc. The final nitration can equally be performed according to well-known methods, e.g. by using concentrated nitric acid. For both aromatic substitutions acetic acid is a suitable solvent. If for the i monoprotection of catechol a mono-acylation in a melt reaction (without a solvent) is chosen, the subsequent introductions of Y, and Y 2 if necessary, and of NO 2 can easily be carried out as an one-pot reaction i. *without isolating intermediates.
The present invention further relates to an intermediate to be used in the method as defined hereinbefore, viz. intermediates of the general formula Y2 i N02 This intermediate of formula XI' cn be prepared from a catechol of above 1; DIR0536 formula XV (i) (ii) (iii) (iv).
(v) by the following process steps: selective protection of one of the free hydroxy groups; optional introduction of one or both of the substituents YI and Y 2 selective nitration of the position ortho to the unsubstituted hydroxy group; deprotection of the protected hydroxy group; formation of the benzodioxole moiety by reaction with a compound of the general formula
R
7
R
8 R/G RIo
(XVII)
:15 wherein: R, and R, have the meanings given above; R, and Rio are each individually chlorine, bromine or
(C-C
4 alkoxy or form together an oxygen atom.
The above reaction steps (iii) and (iv) have been described hereinbefore. The reaction step is preferably carried out by reacting the substituted catechol, obtained after reaction step (iv) and having the general formula
V
S5SS S .oa..
*o a a 25 S S
(XVIII)
Y
2
O-H
NO
2 wherein Yi and Y 2 have the above meanings, with a benzodioxole- forming compound of the above formula XVII, preferably by a methylene-donating agent, such as CH'Cl 2 or CE 2 Br 2 in the presence of an anorganic base, such as NaOH, KOH or K2CO,, in an organic solvent. Suitable organic solvents for this reaction are DMSO, DMF, NMP and toluene, if desired in the presence of a phase-transfer agent. Best results are obtained in DMF as a solvent or toluene in the presence of a phase-transfer agent. The reaction proceeds smoothly at elevated temperature, e.g. at reflux.
16 DIR0536 The invention will now be described in greater detail with reference to the following specific examples.
Example I Mono-acylation of catechol Reaction Scheme: 0 O II OH R O O-C-R OH OH A mixture of 45 mmol catechol and 53 mmol of the acylanhydride is cooled to 2-8 0 C in a water/ice bath. Then 1.5 mmol of an organic base is added as a catalyst. The reaction mixture is stirred for 3 hours at ambient S. 15 temperature. After successive addition of 200 ml ethylacetate and 150 ml water the phases are se-.rated. The organic layer is washed twice with ml 5% aqueous NaHCO solution and. then twice with 50 ml water. The combined aqueous phase is extracted twice with 50 ml ethylacetate. The organic layers are combined and evaporated to dryness under reduced pressure, yielding the desired mono-acylated catechol. The following results are obtained: with acetic anhydride (without an additional solvent) catalyst yield* 25 triethylamine (TEA) diisopropylethylamine (DIEA) 92 triisobutylamine (TIBA) 93 pyridine 67 2,6-lutidine 91 dimethylaniline (DMA) 4-dimethylaminopyridine (DMAP) 84 DMAP/TEA 88 DMAP/TIBA 88 imidazole Yield measured by GC analysis i ii
I
17 DIR0536 In case toluene is used as a solvent for the above TEA-catalyzed reaction, mono-acetyl catechol is obtained in a yield of 86%.
The same above TEA-catalyzed acylation reaction is carried out, using various acylanhydrides; without a solvent except for the monobenzoylation: toluene as a solvent. The following results are obtained: acylanhydride yield* acetic anhydride propionic anhydride butyric anhydride valeric anhydride 93 isobutyric anhydride 87 benzoic anhydride 86 44 yield measured by GC analysis Example II Alkylation of catechol Se Reaction Scheme: OH O-CH-Ar OH OH A. Mono-alkylation of catechol in organic solvent To a mixture of 45 mnol catechol, 58.5 mmol NaHCO 3 and 50 ml solvent, 4 m49.5 nol alkylating agent is added. The mixture is heated to 85 0
C,
while stirring. After a reaction time of 20 hours the reaction mixture is allowed to cool, and successively 200 ml toluene and 150 ml water are added. The layers are separated. The organic layer is washed twice with i 50 ml 5% aqueous NaHCO solution and then twice with 50 ml water. The combined aqueous phase is extracted twice with 50 ml toluene. The collected organic layers are evaporated to dryness under reduced pressure at approx. 40 0 C, yielding the desired catechol mono-ether.
benzoic~h arkdie8 The monobenzylation of catechol with benzylchloride is carried out in
I
18 DIR0536 various solvents, with the following results: solvent yield* ethanol 78 isopropanol 72 methoxyethanol 81 ethyleneglycol/isopropanol 72 Yield measured by GC analysis The above mono-alkylation of catechol is carried out in methoxyethanol as the solvent, starting from various substituted benzylchlorides: (substituted) benzylchloride yield* unsubst. 77 o 4-chloro- 4-methyl- 74 3-chloro- 72 e f 3-methoxy- 76 2,4-dichloro- 2-chloro- 2-fluoro- 73 Yield measured by GC analysis B. In the presence of a phase transfer catalyst, in toluene A mixture of 45 nrol catechol, 4.1 mmol tetrabutylammonium hydrogensulfate (TBAHS) and 25 mmol K 2 CO in 150 ml toluene is refluxed for 2 hours under azeotropic distillation of water (Dean-Stark device).
Then 49.5 mmol of the alkylating agent is added, and the mixture is refluxed for approx. 20 hours while stirring. After allowing the mixture to cool, successively 100 ml toluene and 150 ml water are added. The layers are separated, and the organic layer is washed twice with 50 ml aqueous NaHCO3 solution and then twice with water. The combined water I layers are extracted twice with 50 ml toluene. The collected organic layers are evaporated to dryness under reduced pressure at approx. 40 0
C,
to yield the desired catechol mono-ether.
19 DIR0536 By using benzylchloride as the alkylating agent the desired monobenzyl catechol ether is obtained in a yield of C. Mono-alkylation of catechol without a solvent; presence of phase transfer agent A mixture of 45 mmol catechol, 58.5 mmol KHCO and 4.5 mmol TBAHS is stirred for 15 min at 115 0 C. To this mixture is added 49.5 mmol alkylating agent, and the reaction mixture is stirred at 115 0 C for 2 hours. After the mixture has been allowed to cool, successively 150 ml ethylacetate and 100 ml water are added. The phases are separated, and the organic layer is washed twice with 50 ml 5% aqueous NaHCO and twice with water. The combined aqueous layer is extracted twice with 50 ml toluene. The collected organic layers are evaporated to dryness under reduced pressure at approx. 40 0 C, yielding the desired mono-alkyl ether 15 of catechol.
Instead of TBAHS tetrabutylammonium bromide and tetrabutylammonium chloride can be used as phase transfer agents.
The following results are obtained: *ooz (substituted) benzylchloride yield* unsubstituted 72 3-chloro- 71 4-chloro- 72 2,4-dichloro- 76 4-nitro- Yield measured by GC analysis o" D. Alkylation of catechol in water.
To a mixture of 45 mmol catechol, 58.5 mmol NaHCOQ and 50 ml water is added 49.5 mmol alkylating agent. The mixture is refluxed for 1.5 to 22 hours while stirring. After successive addition of 200 ml ethylacetate and 100 ml water the layers are separated. The organic layer is washed twice with 50 ml 5% aqueous NaHCO 3 and twice with water. The combined aqueous layer is extracted twice with 50 ml toluene. The collected organic layers are evaporated to dryness under reduced pressure at approx. 400C, yielding the desired catechol mono-alkyl ether.
The following results are obtained: Mro DIR053G alkylating agent ref lux time (h) benzylchJloride 1.5 3 -chlorobenzylchloride 3.5 2- chlorobenzyl chloride 6 2- fluoro-benzylchloride 5 2, 4-dichlorobenzylchl. 6 3 -methoxybenzyl chloride 22 Yield measured by GC analysis yield'(% .67 82 69 87 Exanple III Mnosilylation of catechol Reaction Scheme: 215 Poo* O~yl
OH
CH
3
CH
3 (04 3 ),CSWI(CH l H 3
CH
3 OH3
I'
To a mixture of 45 nuol catechol and 54 imnol tert butyldimethylsilyl chloride in 50 ml methyl tert.-butyl ether (MTBE) 45 rml triethylanine is added in 10 min. The reaction mixture is refluxed for 16 hours while stirring and then allowed to cool. After successive addition of 150 ml MTflBE and 150 ml water the layers are separated. The organic layer is washed twice with 50 ml 5% aqueous NaHCO 3 solution and twice with 50 ml water. The combined aqueous layer is extracted twice with 50 ml MIBE.
The collected organic layers are evaporated to dryness under reduced pressure at approx. 401C, yielding 10.6 g of the desired catechol mono- (trialkylsilyl) ether as a yellow oil with a purtity of 87% (91% yield) 'H-NMP. CDC1,) 0.27 Cs, 6H), 1.02 Cs, 9H), 6.74 1H, J=8Hz), 6.82 Cd, 1H, J=8Hz), 6.86 lH, J=8Hz), 6.93 Cd, 1H, J=8Hz).
Exanple IV Preparation of 5-chloro-3-nitrocatecbol Reaction Scheme: '.1
I
0 Qr CH
H
3 al
H
OH
21 DIR0536 a) Preparation of 110 g catechol (1 mol) is dissolved in 110 ml acetic acid. 4.4 ml (0.03 mol) triethylamine and 110 ml (1.19 mol) acetic anhydride is added and the mixture is heated to 80°C during 60 minutes. After cooling down till 330 ml acetic acid is added and 82.5 ml (1.04 mol) surfuryl chloride is dosed in about 25 minutes, keeping the temperature below followed by stirring for 40 minutes at A solution of 115.5 mnl (1.8 mol) of 70% HN03 in 165 ml of acetic acid is prepared, keeping the temperature below 20°C. To this mixture the above i obtained chlorination reaction mixture is dosed in 60 minutes at 15-20°C, i followed by an additional stirring for 30 minutes at 15-20°C. 275 ml toluene and 550 ml water are added and the layers are separated. The water layer is extracted with 140 ml of toluene (3x) and the combined r° I' organic layers are washed with 140 ml water The toluene is removed SIi by vacuum distillation, 200 ml of ethanol is added and removed by vacuum distillation. After addition of 275 ml of ethanol, heating the mixture i until all material has been solved, cooling down to 0-5°C under stirring and stirring for an additonal hour the crystals formed are filtered, washed with cold ethanol and dried to yield 106.5 g of 99% pure 3- .nitro-5-chloro-mono-acetylcatechol.
'H-NMR: DMSO/CDC1 3 3/1) 7.07 1H, J=2Hz), 7.34 1H, J=2Hz).
i 25 b) Preparation of :The crystallate obtained above is suspended in 200 ml water. In S' ,,minutes 82 ml 50% NaOH is added under stirring, keeping the temperature below 30°C, followed by an additional stirring of 15 minutes. In ten minutes 155 ml concentrated hydrochloric acid is added, keeping the temperature below 35°C, followed by cooling down to 25°C. 135 ml methylt-butyl ether (MTBE) is added and the mixture is stirred for 15 minutes, followed by separation of the layers. The water layer is extracted twice with MTBE. The combined organic layers are concentrated by evaporation to yield a 85.6 g (45% calculated on starting catechol) of a yellow, solid product with a purity of 99%. 1 22 DIR0536 Example V lSynthesis of 6-Chloro-4-nitro-l,3-benzodioxole Reaction Scheme:
OH
NO
2
NO
2 5-Chloro-3-nitro-catechol can be prepared in two manners, viz. from salicylaldehyde, by a successive chlorination, nitration and Dakin oxidation according to the method dexcribed by M. Nikaido et al., J.
Org. Chem. 1984, 49, 4740-1, or by starting from monoprotected catechol as described in Example I.
Synthesis of the title compound by using CH 2 Cl 2 Under N 2 8.0 g of NaOH (powdered) is dissolved in 80 ml of DMSO, or, .15 alternatively, in N-methylpyrrolidone (NMP) at 80°C. In about 15 min a H solution of 20.0 g of 5-chloro-3-nitro-catechol in 20 ml DMSO (NMP) and H 100 ml CHC 2 is added at 80°C. The reaction mixture is heated 130°C for 8-30 hours while stirring. After cooling down to room temp., successively 200 ml water and 400 ml toluene are added. Stirring for min., separation of the layers, and extraction of the water layer with 100 ml toluene yields a combined organic phase, which is washed twice .*with 50 ml satd. aqueous NaCI solution, with 50 ml water and twice with 100 ml satd. aqueous NaCl solution. After evaporation of the solvent S" (100 mbar, 40°C), the desired product is obtained in a yield of 70.3%; purity 84%.
H-NMR DMSO/CDC1 3 4/1) 6.39 2H), 7.46 1H, J=2Hz), 7.58 1H, J=2Hz) Synthesis of the title compound by using CHBr Under N 2 200 g of 5-chloro-3-nitro-catechol is dissolved in 1050 ml DMF.
To this solution are added 204 g anhydrous, powdered KzCO 2 and 220 ml
CH
2 while stirring the mixture. The reaction mixture is refluxed for 1 hour (140°C) and then cooled down to 80°C. After addition of 800 m1 water, the mixture is cooled down to room temp. The crystalline product is filtered off and washed successively with 2 x 600 ml water, 2 x 250 ml ethanol, and 2 x 300 ml n-hexane. After drying under reduced pressure at 60°C, the desired product is obtained in a yield of 82%; purity Equally successful results are obtained in toluene as the solvent i 23 DIR0536 instead of DMF, under phase transfer conditions.
Example VI Conversion of monoprotected chloro-nitrocatechol to compound with formula VII Reaction Scheme: c+ oi I o
I
1OH 0
R
4 N0 2 1? 3 N0 2 0 R4 Reaction with enantiomerically pure glycidyl compounds (Z is nosyl;
R
3 and RP together form a valence bond; Rs is benzyl) 5-Chloro-3-nitro-monobenzylcatechol (8.94 mmol), K 2 C0 3 (9.78 mmol), TBAHS j (23 mol%) and 100 ml toluene are stirred under reflux during 30 minutes under simultaneous removal of water (Dean-Stark device). The mixture is cooled to 80 0 C and -glycidylnosylate (8.94 mmol) is added. The mixture I is stirred at 100 0 C during 30 minutes, cooled down and diluted with S ethylacetate/brine. The water layer is extracted with ethyl acetate two times. The combined organic layers are washed with brine dried over MgS04 and filtered over 30 g of silica. The filter is washed with ethyl acetate and the filtrate is reduced by evaporation. The residue is ".crystallized from 20 ml 96% ethanol, yielding 2.7 g yellowish needles with an ee 97% (determined with NMR) 1 H-NMR (8,CDC1 3 2.61 (dd, 1H, J=5Hz, J=3Hz), 2.80 (dd, 1H, '25 J=5Hz), 3.33 (cluster, 2H), 4.24 1H), 5.13 2H), 7.15 1H, J=2Hz), 7.36 1H, J=2Hz), 7.37-7.48 (cluster, The same reaction is carried out in a solvent mixture of DMF/toluene 1/1 without a phase transfer agent. After 18 hours at 110°C the desired product is obtained in a yield of 73%; ee=98%.
A corresponding experiment starting from (R)-glycidyltosylate, in toluene and with TBAHS, yields after 46 hours 82% of the desired product; ee=98%.
The corresponding (S)-glycidyl ether of 5-chloro-3-nitro-monobenzylcatechol is obtained by a corresponding reaction of the starting monoprotected catechol with -glycidyltosylate in toluene in the presence of TBAHS. Yield, after 15 hours, 77%; ee=98%. In a DMF/toluene (1/1) i mixture without TBAHS the same product is obtained (ee=98%) after 46 -~r 24 DIR0536 hours in a yield of 73%.
Derivatization of 5-chloro-2-hydroxy- 3 -nitrophenol-benzylether with a solketal compound (Z is nosyl; R, and R, together constitute a biradical of the formula -C(CH 3 2 Rs is benzyl).
In a corresponding manner as described under the solketal ether of 5-chloro-3-nitro-monobenzylcatechol is prepared: 1.1-1.2 eq. K,C0, mol% TBAHS, toluene, reflux. By using -solketal-nosylate the desired (S)-solketal ether of 5-chloro-3-nitro-monobenzylcatechol is obtained in a yield of 83%; ee=98%.
The corresponding (R)-solketal ether is obtained by using the i solketal-tosylate in a yield of 68% after a reaction time of 38 hours; ee=98%. The yield can be improved to 80% after 49 hours reflux.
*15 Derivatization of 5-chloro-2-hydroxy-3-nitrophenol-benzylether with the methoxy isopropyl ether of l-chloro-3-tosyloxypropan-2-ol (TCA-MIP .ether) (Z is tosyl; R, is C(CH 3 2 0CH 3 R4 is chloro; R, is benzyl) In a corresponding manner as described under the above compound is prepared from 5-chloro-3-nitro-monobenzylcatechol and chiral TCA-MIP ether; KC0 3 TBAHS, toluene, 24 hours reflux. The desired enantiomerically pure product is obtained in a yield of 53%.
Example VII 25 Conversion of monoprotected chloro-nitrocatechol to compound with formula VIIa Reaction Scheme: C OR 5 C 0 CH 2 0R 5 c OH 0 o
NO
2
NO
2 Reaction with enantiomerically pure glycidyl compounds (Z is nosyl; R and R, together form a valence bond; is benzoyl).
Preparation of -7-chloro-2,3-dihydro-5-nitro-benzodioxin-2-4 methanol benzoic ester.
g 5-chloro-3-nitro-mono-benzoylcatechol (6.3 mmnnol), 0.9 g K 2 CQ (6.3 DIR0536 mmol) and 0.2 g TBAHS (0.63 mmol) are suspended in 75 ml toluene and refluxed under simultaneous removal of water (Dean Stark device). After removal of 25 ml toluene the orange mixture is cooled to 60 0 C and 1.7 g S (+)-nosyl glycidyl ester is added. After refluxing during 23 hours the reaction mixture is diluted with saturated brine (10 ml) and water ml) and extracted with 50 ml ethyl acetate. The organic layer is washed with 10 ml saturated brine (2x) and with acidified water (2x(15 ml and 2.5 ml 2N HC1)). The organic layer is reduced by evaporation to yield 2.52 g of an orange/brown syrup. The syrup is puriefied by flash chromatography over a 4.0 x 30 cm column of silica gel with petroleum ether/diethylether The product -7-chloro-2, benzodioxin-2-methanol benzoic ester is obtained as a yellow solid: 0.75 g M.p. 83-88 0 C; ee=96%; [a] 25 +110.3 (EtOAc, c 10 g/l, d cm).
IH-NMR CDC1,) 8.02 7.60 7.52 7.46 7.17 4.62 4.27 (dd).
Example VIII Conversion of aminoprotected chloro-nitro-aminophenol to compound with formula X e Reaction Scheme: oc N02 I TsO\- 7 A suspension of N-acetyl-2-hydroxy-3-nitro-5-chloro-aniline (34.6 mmol), KC0 3 (40.6 mnol), 80 ml NMP and 80 ml toluene is refluxed during one hour under removal of water (Dean Stark device). The toluene is distilled off and the teaction mixture is cooled down to 110 0 C. glycidyltosylaat (40.8 mmol) is added. The reaction mixture is stirred at 120 0 C during 4.5 hours, followed by cooling and dilution with water and ethylacetate and coorecting the to 4 to 6 with diluted hydrochloric acid. The water layer is extracted twice with ethylacetate.
The combined organic layers are washed three times with brine and dried
I
26 DIR0536 over MgSO 4 After filtration and evaporation of the solvent under reduced pressure, 10.8 g of a dark brown oil is obtained. After chromatography over SiO, (ethylacetate/petrol ether 1:3) 3-acetoxymethyl-6-chloro-8nitro-2,3-dihydro-l,4-benzoxazine is obtained in a yield of 42%. ee 86%. [ao 20 -11,6 (c=0,86, 96% ethanol), mp 76-84 0
C.
1H-NMR CDC1,) 2.12 3H), 3.79 1H), 4.07 4.35 (cluster, 4H), 4.58 (broad s, 1H, NH), 6.78 1H, J=2Hz), 6 7.21 1H, J=2Hz).
Example IX Derivatization, starting from substituted 1,3-benzodioxole Reaction with solketal derivatives.
Reaction Scheme: "ci c o
-OH
NOHO
O
2 0 0 6-Chloro-4-nitro-l,3-benzodioxole is derivatized by a reaction with chiral solketal, i.e. chiral 4-hydroxymethyl-2, 2-dimethyl-l, 3-dioxolan.
The reaction is performed in a suitable organic solvent, such as DMF, NMP or toluene, in the presence of a base, e.g. IKC0 3 Li 2
CO
3 NaH, etc.
If toluene is used as a solvent, a phase transfer agent is additionally preferred, e.g. TBAB or TBAHS.
25 So, 4.6 g (3 eq) powdered K 2 C0 3 is suspended in 20 ml DMF under nitrogen at room temperature. 1.46 ml S-solketal (1 eq) is added to this suspension, followed by a solution of 2.2 g 6-chloro-4-nitro-l,3benzodioxole in 20 ml DMF. The mixture is heated to 900C during 70 hours.
After cooling down to room temperature 50 ml toluene and 50 ml saturated NaC1 solution are added, and the mixture is stirred during 5 minutes.
The pH is adjusted to 5-6 with about 15 ml of 2N HC1 solution. The layers are separated and the water layer is extracted (2x) with 25 ml toluene. The concentrated organic layers are washed (3x) with 25 ml saturated NaCl solution. The organic layer is concentrated to evaportion to yield 3.27 g (4-chloro-2-hydroxy-6-nitro)-phenoxymethyl- 2,2-dimethyl-l, 3-dioxolan.
1 H-NMR CDCI 3 1.48 3H), 1.54 3H); 3.91 1H, J~8Hz), 4.08 c- 27 DIR0536 (dd, 1H, J-6Hz, J-11), 4.18 1HI, J-8Hz), 4.37 (dd, 1H, J=llHz, J=3Hz), 4.52 1H), 7.18 lH, J=2Hz), 7.36 1H, J=2Hz), 8.74 (s, 1H) After a reaction time of 5 hours in NMP as the solvent the same product can be obtained in a yield of 79%.
The corresponding -solketal ether is prepared in a corresponding manner, using (R)-solketal as the starting material.
In a corresponding manner enantiopure 4-chloro-2-hydroxy-6-nitrophenoxymethyl-2,2-diispropyl-1,3-dioxolan compounds can be obtained starting from 6-chloro-4-nitro-, 3-benzdioxole and chiral 4hydroxymethyl-2, 2-diisopropyl-1, 3-dioxolan.
Reaction with glycidol Reaction Scheme: S8C C I HO/C\
OH
00 too*
~NO
2
NO
2 solution of 6-chloro-4-nitro-, 3-benzodioxole (2.48 mmol) in 10 ml DMF is cooled down in an icebath. A 60% NaH dispersion (5.5 mmol) in mineral oil is added, immediately followed by a solution of (S)-glycidol (3.13 4 mmol, ee=84%) in 5 ml DMF. After 1,5 hours stirring at 0 0 C ice is added ice together with brine and 2N HC1 until the pH is lower then 5. The ,i water layer is extracted three times with ethylacetate. The combined 25 organic layers are washed three times with brine, dried on MgSO 4 and filtrated. After filtration over A1,Q0 and evaporation of the solvent 6, under reduced pressure, 0.4 g of a dark brown oil is obtained. chloro-2, 3-dihydro-5-nitro-benzodioxin-2-methanol is obtained in a yield of 35% after chromatography over Si 2 ee=74%.
Example X Deprotection and ring-closure; formation of subst. benzodioxin-2methanol and related compounds.
Reaction Scheme:
OR
5 Cl 0 CH 2
OH
-Y
NO NO4 28 DIR0536 The product prepared in Example VI under is deprotected under simultaneous epoxide ring-opening by mineral acid. The chloro-nitromonobenzyloxyphenyl (R)-glycidyl ether can be converted easily to the corresponding catechol monochlorohydrine by reflux in a propanol/water mixture during 48 hours under the influence of 30 eq. HC1; yield 87%; ee=98%; after 3 hours reflux the deprotection is already 83%. The corresponding (S)-enantiomer is formed in 83% yield (ee=86%) after 9 hours reflux. Alternatively, acetic acid can be used as the solvent.
Then the deprotection and epoxide ring-opening proceed smoothly already at 35 0 C in 1 hour.
The above chlorohydrine is ring-closed under basic conditions, yielding the desired chiral 7-chloro-2,3-dihydro-5-nitro-benzodioxin-2-methanol in quantitative yields. The ring-closure is easily carried out in ethanol/water as the solvent at room temp. under the influence of '15 approx 2 eq. of NaOH or KOH; reaction time approx. 18 hours.
Deprotection and ring closure of the solketal ether obtained according to Example VI The deprotection is carried out in a suitable solvent or solvent mixture such as acetic acid, under the influence of HBr or HC1, preferably at 'o" t slightly elevated temperature. So the (R)-solketal ether of monobenzyl chloro-nitrocatechol is debenzylated under simultaneous cleavage of the ispropyl group of the solketal moiety to the corresponding bromohydrin •acetate with 45% HBr (8 eq.) in acetic acid at 35 0 C; 88% yield after *o 0.25 hour. The corresponding (S)-solketal ether is deprotected in hour (yield 78%).
The subsequent ring-closure reaction of the compound obtained in this manner is carried out under alkaline conditions. So the desired chloro-2,3-dihydro-5-nitro-benzodioxin-2-methanol is obtained by a ringclosure in ethanol with 2N NaOH (16 eq.) in 1 hour at room temp.; ee=96%. Yield, including deprotection,
I
The corresponding (S)-stereoisomer is obtained in a yield of (ee=92%) by reaction with 7 eq. 2N NaOH in ethanol at 23 0 C after 2 hours.
The solketal ethers, prepared according to Example IX, are successively subjected to a solketel cleavage, preferably with HC1 or HBr in acetic 29 DIR0536 acid to the corresponding halo-acetate, and to a ring-closure reaction as described above. Overall yields up to 80%. Stereoselectivity: ee=89%.
In the same manner the dialkylsolketal ethers of Example IX are ringclosed, yielding the desired 7-chloro-2,3-dihydro-5-nitro-benzodioxin-2methanol enantiomer in overall yields of approx. 55%; ee=98%.
The TCA-MIP ether obtained as described in Example VI(c) is subjected to the same deprotection-ringclosure reactions as described above: 45% HBr/AcOH and 2N NaOH (ethanol) successively. The chiral subst. benzodioxan-methanol is obtained in an overall yield of having an ee of
C
r a C C b0:: i
Claims (13)
1. A method for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer, wherein a substantially pure enantiomer of the general formula CH 2 -OH wherein X is 0, S, NH or N-(C 1 -C 4 )alkyl; Y, and Y, are each independently hydrogen or substituents selected from halogen, (Ci-C 4 )alkyl, (C-C 4 )alkoxy, (Cl-C 4 haloalkyl, formyl, nitro and cyano; the C*-atom has either the R or the S configuration; is prepared from a compound of the general formula INU 2 (II) wherein: X, Y, and Y 2 have the same meanings as defined above; R, is hydrogen or a suitable protective group; R2 is hydrogen; or wherein R, and R, together form an optionally mono- or di- (C-C)alkyl substituted methylene bridge; by the following successive reaction steps: reaction with a compound of the general formula 0 R4 R3 (III) wherein: Z is a hydroxy group or a suitable leaving group; R 3 is a hydroxy-protective group; 4r- l 7 ;1 DIR0536 R, is a halogen atom; or wherein R 3 and R 4 together constitute a valence bond or a biradical of the formula 2 wherein R, is a straight or branched (C 1 -C 4 )alkyl group; the C*-atom has either the R or the S configuration; after which reaction a conpound is formed of the general formula X-RI Y 1 a Y2 i O (IV) NO 2 OR 3 wherein: X, Yi, Y 2 R 3 and R, have the above meanings; and R, is hydrogen or a protective group; (ii) subjection of the compound formed to a deprotection/ring- closure reaction; (iii) optionally deprotection of the hydroxy group of the ring-closed product.
2. A method as claimed in claim 1, wherein a substantially pure enantiomer of the general formula I as defined in claim 1, wherein X is 0, is prepared by reaction of a catechol derivative of the general formula O-Rs Yi I (V) Y2 O O-H NO 2 wherein: Y, and Y 2 have the meanings given in claim 1; and R 5 is a suitable hydroxy-protective group; with a compound of the general formula (VI) 0 R4 R 3 32 DIR0536 wherein: R 3 and R 4 have the above meanings; and Z' is a halo or a sulphonate leaving group, preferably selected from tosyloxy, nosyloxy and mesyloxy; after which reaction the intermediate obtained, having the general formula (VII) NO 2 OR 3 is subjected to the successive reaction steps (ii) and (iii) as defined in claim 1.
3. A method as claimed in claim 1, wherein a substantiall.y pure enantiomer of the general formula I as defined in claim 1, wherein X is O, is prepared by reaction of a catechol derivative of the general formula O-Rs' (Va) O-H NO 2 i wherein: Y, and Y 2 have the meanings given in claim 1; and .o R' is a hydroxy-protective group selected from the group consisting of (C1-C,)alkylcarbonyl and arylcarbonyl, wherein the aryl group is optionally substituted with one or more substituents selected from the group consisting of C 4 alkoxy and halogen; with a compound of the general formula Z (VI) 0 R 4 wherein: R 3 R 3 and P have the above meanings; and 33 DIR0536 Z' is a halo or a sulphonate leaving group, preferably selected from tosyloxy, nosyloxy and mesyloxy; after which reaction the intermediate obtained, having the general formula 0 *CH 2 -ORs' 0 (VIIa) NO 2 is subjected to deprotection of the hydroxy group of the ring-closed product.
4. A method as claimed in claim 1, wherein a substantially pure enantiomer of the general formula I as defined in claim 1, wherein X is NH or N- (C,-C 4 )alkyl, is prepared by reaction of a compound of the general formula 0 R 6 N-RS (VIII) "2 O-H wherein: 2 Y, and Y have the meanings given in claim 1; and Rs' is a suitable amino-protective group; R is hydrogen or (C-C 4 )alkyl; *,JB with a compound of the general formula Z, (XI) 0 R 4 wherein: R 3 R, and R, have the above meanings; and Z' is a halo or a sulphonate leaving group, preferably selected from tosyloxy, nosyloxy and mesyloxy; after which reaction the intermediate formed, having the general formula ai! 34 DIR0536 N CH 2 -OR 5 Y2T NO 2 is subjected to the deprotection of the hydroxy group of the ring-closed product.
5. A method as claimed in claim 1, wherein a substantially pure enantiomer of the general formula I as defined in claim 1, wherein X is 0, is prepared by reaction of a benzodioxole compound of the general formula (XI) Y.^rV 7 0 *a o 0 o o* *o wherein: Y and Y 2 have the meanings given in claim 1; and R 7 and R, are each independently hydrogen or methyl; with a chiral building block of the formula 0aaa o a 0**a 25 r. *4 a Oa*c HOX (XIIa) or HO0 0 0 R 11 R 1 i (XIIb) wherein: R 11 is a straight or branched (Ci-C 4 )alkyl group; the C*-atom has either the R or the S configuration; after which reaction the intermediate obtained, having the general formula or Y or 11 rarrPC~ I _II r. :b ci.c__ Pb II~III i IYB F: (XIIlla) (XIllb) is subjected to the reacting step ii) as defined in claim 1.
6. A method as claimed in any one of claims 1, 2, 4 or 5, wherein the ring- closure reaction (ii) is carried out in an apolar organic solvent with the aid of a phase transfer catalyst.
7. An enantiomerically pure compound to be used as an intermediate in the method of claim 1, having the general formula 10 *OcstO 5*46 (IV) wherein: 9 15 *4*4 0 *s S S 0 Y 1 Y 2 X, R 3 and R4,have the meanings given in claim 1, and R 1 has the meaning given in claim 1. the C*-atom has either the R or the S configuration;
8. A method of preparing a compound of the general formula IV as defined in cliam 7, wherein a compound of the general formula X- R1 ^Y 2O-R 2 NO 2 (II) wherein the symbols have the meanings given in claim 1; is reacted with a compound of the general formula i Ii IC C\WWORILONAOTHERSPECItSPl001 DO 36 z 0\ R 4 R3 (II!) wherein the symbols also have the meanings given in claim 1.
9. A method of preparing a compound of the general formula Vila as defined in claim 3, wherein a compound of the genral formula 0-ee Y2O H 1 O NO 2 (Va) wherein the symbols have the meanings given in claim 3; is reacted with a compound of the general formula (VI) 0 R4 15 R 3 (Vl) wherein the symbols also have the meanings given in claim 2. A method of preparing a catechol derivative, to be used in the method of claim 2 and having the general formula Ri4 o (la-\WNWORD\ILONA\OTHER\SPEC'SPIOO8.OC 37 DIR0536 O-Rq Y Y I (xIv) 2 ^O-H NO 2 wherein: Y, and Y 2 have the meanings given in claim 1, and R, is an optionally substituted benzoyl group, a (Ci-C 4 alkylcarbonyl group or a tri(C,-C 4 )alkylsilyl group; A by reaction of a substituted catechol of the general formula O-H \O-H .:15 (XV) wherein: Yi and Y, have the above meanings, and p and q are 0 or 1; with a compound of the general formula (R')20 or R,'Hal or (R, 4 ),SiHal wherein: SR' is an optionally substituted benzcyl group or a (Ci-C)alkyl- carbonyl group; R 4 is (C-C 4 )alkyl; and Hal is halogen; in the presence of an organic base, preferably a tert. amine or a mixture of organic bases, in a catalytic amount; wherein the reaction is carried out in an apolar organic solvent or without a solvent, after which the compound obtained, having the general formula O-Rg (X(a) O-H (XVIa '1 f:! -i 38 is successively subjected to an aromatic substitution reaction to introduce substituents Y, and Y 2 into the aromatic nucleus, if necessary, and to a nitration.
11. A compound to be used as in intermediate in the method of claim having the Y O, /R 7 o 0O R 8 NO 2 (XI) ~g a P. 15 *a 20 *S9 9s wherein Y, and Y 2 have the melanings given in claim 1; and R 7 and R 8 are each independently hydrogen or methyl.
12. A process for the preparation of the compound with the general formula XI as defined in claim 11, wherein a catechol compound with the general formula XV as defined in claim 11 is converted by the following reaction steps, selective protection of one of the free hydroxy groups; (ii) optional introduction of one or both of the substituents Y, and Y 2 (iii) selective nitration of the position ortho to the unsubstituted hydroxy group; deprotection of the protected hydroxy group; formation of the benzidioxole moiety by reaction with a compound of the general formula R 7 /R 8 C R 9 R 1 (XVII) wherein: R 7 and R8 have the meanings given in claim 11; R 9 and Rio are each individually chlorine, bromine or (C 1 -C 4 alkoxy or form together an oxygen atom. IC C:\WINWORDWLONA\OTHERISPECSP1001.DOC 39
13. A method according to claim I substantially as hereinbefore described with reference to any one of the examples.
14. A compound according to claim 7 substantially as hereinbefore described with reference to any one of the examples. DATED: 18 November, 1998 PHILLIPS ORMONDE FITZPATRICK Attorneys for: DUPHAR INTERNATIONAL RESEARCH B.V. 10 *4 o 0 CV.. ft 9* ft Oft ~1* S 0 9* 0# V 9 85 4* 0* V V., 4 0 0 9 4 0~~ 4 9V.V S 4 ICC:.%WWOROLONAIOTHERISPEClSPOO8,OOC i i DIR0536 Abstract The invention relates to a method for the stereoselective preparation of a hetero-bicyclic alcohol enantiomer, characterized in that a substantially pure enantiomer of the general formula X CH 2 -OH Y2 O (I) NO2 wherein X is O, S, NH or N- (Ci-C 4 )alkyl; Y, and Y 2 are each independently hydrogen or substituents selected from halogen, (Ci-C 4 )alkyl, (C,-C 4 )alkoxy, (Ci-C 4 haloalkyl, formyl, nitro and cyano; the C*-atom has either the R or the S configuration; is prepared from a compound of the general formula X-RI Y 1 NO 2 (C-C,)alkyl substituted methylene bridge; 5 by the following successive reaction steps: reaction with a compound of the general formula (III) wherein Z is a hydroxy group or a suitable leaving group, R, is a hydroxy-protective group and RP is a halogen atom; or wherein R 3 and R, together constitute a valence bond or a biradical of the formula -C wherein R 1 is a straight or branched (C-C 4 )alkyl group and wherein the Cf-atom has either the or the S onfiguration; (ii) subjection of th compound formed to a deprotection/ring- 1 closure reaction; DIR0536 (iii) optionally deprotection of the hydroxy group of the ring-closed product. The invention further relates to enantiomerically pure intermediates, the pr~eparation of these intermediates and the preparation of a starting conrpound. 0** 0 s*
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CA2256681A1 (en) * | 1997-05-12 | 1998-11-19 | Yoshiro Furukawa | Process for producing 1,4-benzodioxane derivatives |
KR100780538B1 (en) * | 2006-08-02 | 2007-11-30 | 안국약품 주식회사 | Process for the preparation of chiral 2-hydroxymethyl-1,4-benzodioxane compound |
WO2009087505A2 (en) * | 2007-12-31 | 2009-07-16 | Daniel Farb | Placing water turbines in water flows |
WO2010079423A1 (en) * | 2009-01-12 | 2010-07-15 | Council Of Scientific & Industrial Research | Inhibitors of phosphatidylinositol-3-kinase (pi3) and inducers of nitric oxide (no) |
US9650322B2 (en) | 2012-07-26 | 2017-05-16 | Rhodia Operations | Method for producing alkoxyhydroxybenzaldehyde |
FR2993881B1 (en) * | 2012-07-26 | 2014-08-15 | Rhodia Operations | PROCESS FOR THE PREPARATION OF ALKOXYPHENOL AND ALKOXYHYDROXYBENZALDEHYDE |
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EP0786459A1 (en) | 1997-07-30 |
CA2195724C (en) | 2006-05-16 |
NO970281D0 (en) | 1997-01-22 |
CA2195724A1 (en) | 1997-07-26 |
HK1000698A1 (en) | 2002-12-13 |
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US5948909A (en) | 1999-09-07 |
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UA58483C2 (en) | 2003-08-15 |
CZ20697A3 (en) | 1997-08-13 |
CN1139586C (en) | 2004-02-25 |
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HU9700200D0 (en) | 1997-03-28 |
NZ314103A (en) | 1997-12-19 |
IL120055A0 (en) | 1997-04-15 |
HUP9700200A3 (en) | 1999-03-01 |
HUP9700200A2 (en) | 1998-12-28 |
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DE69714875T2 (en) | 2003-04-30 |
TW363059B (en) | 1999-07-01 |
EP0786459B1 (en) | 2002-08-28 |
MX9700662A (en) | 1998-06-28 |
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